Lipid-free Formulation Research Articles

High-Loading Self-Assembling Peptide Nanoparticles as a Lipid-Free Carrier for Hydrophobic General Anesthetics.

PurposeTypical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated.MethodsThioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY’s capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY.ResultsStable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed.ConclusionGQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.

Oral administration of tipranavir with long-chain triglyceride results in moderate intestinal lymph targeting but no efficient delivery to HIV-1 reservoir in mesenteric lymph nodes

The introduction of combination antiretroviral therapy (cART) led to substantial improvement in mortality and morbidity of HIV-1 infection. However, the poor penetration of antiretroviral agents to HIV-1 reservoirs limit the ability of the antiretroviral agents to eliminate the virus. Mesenteric lymph nodes (MLNs) are one of the main HIV-1 reservoirs in patients under suppressive cART. Intestinal lymphatic absorption pathway substantially increases the concentration of lipophilic drugs in mesenteric lymph and MLNs when they are co-administered with long-chain triglyceride (LCT). Chylomicrons (CM) play a crucial role in the intestinal lymphatic absorption as they transport drugs to the lymph lacteals rather than blood capillary by forming CM-drug complexes in the enterocytes. Thus, lipophilic antiretroviral drugs could potentially be delivered to HIV-1 reservoirs in MLNs by LCT-based formulation approach. In this study, protease inhibitors (PIs) were initially screened for their potential for intestinal lymphatic targeting using a computational model. The candidates were further assessed for their experimental affinity to CM. Tipranavir (TPV) was the only-candidate with substantial affinity to both artificial and natural CM in vitro and ex vivo. Pharmacokinetics and biodistribution studies were then performed to evaluate the oral bioavailability and intestinal lymphatic targeting of TPV in rats. The results showed similar oral bioavailability of TPV with and without co-administration of LCT vehicle. Although LCT-based formulation led to 3-fold higher concentrations of TPV in mesenteric lymph compared to plasma, the levels of the drug in MLNs were similar to plasma in both LCT-based and lipid-free formulation groups. Thus, LCT-based formulation approach alone was not sufficient for effective delivery of TPV to MLNs. Future efforts should be directed to a combined highly lipophilic prodrugs/lipid-based formulation approach to target TPV, other PIs and potentially other classes of antiretroviral agents to viral reservoirs within the mesenteric lymphatic system.

Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations.

Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

Effect of Lipid Composition in Propofol Formulations: Decisive Component in Reducing the Free Propofol Content and Improving Pharmacodynamic Profiles.

Current endeavor was aimed towards studying significance of lipid composition on free propofol concentration in aqueous phase and associated pain on injection. Three different nanoformulations, namely long-chain triglyceride (LCT)/medium-chain glyceride (MCG)-based nanoemulsion (ProNano), MCG-based self-nanoemulsifying formulation (PSNE), and lipid-free nanoformulation (PNS) were accessed for the same. In vitro and in vivo performances of developed formulations were compared with Diprivan®. ProNano showed minimum free propofol concentration (0.13%) and hence lower pain on injection (rat paw-lick test, 6 ± 2s) compared to Diprivan®, PSNE, and PNS (0.21%, 0.23%, and 0.51% free propofol, respectively, and rat paw-lick test; 12 ± 3, 14 ± 2, and 22 ± 3s, respectively). These results conjecture the role of MCG in effective encapsulation of propofol. Anesthetic action assessed by measuring duration of loss of righting reflex (LORR), which was found similar in case of ProNano and PSNE (14 ± 3 and 15 ± 3min, respectively) compared to Diprivan® (13 ± 3min). In case of lipid-free formulation, PNS, extended anesthetic action (21 ± 2min) was observed which may be due to sustained release of propofol from nanosponges. Studies on effect of lipoproteins on propofol release highlighted significance of HDL (100% release with maximum concentration of about 1.2μg/ml of HDL) from all three formulations.

Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: Dexanabinol and PRS-211,220

The aim of this article was to investigate the role of intestinal lymphatic transport in the oral bioavailability of two structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. For this purpose, the long chain triglyceride (LCT) solubility and affinity to chylomicrons ex vivo of both cannabinoids were evaluated. Their oral bioavailability was assessed in rats following administration in a lipid-free and a LCT-based formulation. The intestinal lymphatic transport of these two molecules was also directly measured in a freely moving rat model. LCT solubility of dexanabinol and PRS-211,220 was 7.9 ± 0.2 and 95.8 ± 5.3 mg/g, respectively. The uptake by chylomicrons was moderate (31.6 ± 5.2%) and high (66.1 ± 2.4%), respectively. The bioavailability of dexanabinol (37%) was not affected by LCT solution, whereas administration of PRS-211,220 in LCT improved the absolute oral bioavailability three-fold (from 13 to 35%) in comparison to the lipid-free formulation. The intestinal lymphatic transport of dexanabinol and PRS-211,220 was 7.5 ± 0.8 and 60.7 ± 6.8% of the absorbed dose, respectively. In conclusion, despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibited a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. The low lymphatic transport of dexanabinol is likely driven by relatively lower affinity to chylomicrons and lower LCT solubility.

Pain on Injection of Lipid-Free Propofol and Propofol Emulsion Containing Medium-Chain Triglyceride: A Comparative Study

Pain on injection of propofol continues to be a problem for anesthesiologists. A lipid-free formulation of propofol and a propofol emulsion containing medium-chain triglyceride have become available in the Indian market. We performed this study to assess the pain on injection of propofol emulsion containing medium-chain triglyceride as the lipid carrier and lipid-free propofol formulation. One-hundred-thirty adult patients were randomly assigned to one of two groups: Group I received propofol emulsion containing medium-chain triglyceride and Group II received lipid-free propofol. One fourth of the total calculated induction dose was injected over 5 s in the largest vein on the dorsum of a hand. Pain was assessed using verbal response and behavioral signs. Both formulations caused pain on injection. However, the lipid-free propofol solution produced frequent (89%) and severe pain on injection compared with the emulsion containing medium-chain triglyceride (40%). Pain on injection of two formulations of propofol was compared. A lipid-free formulation produced more pain on injection as compared with the emulsion containing medium-chain triglyceride.

A Novel, Lipid-Free Nanodispersion Formulation of Propofol and Its Characterization

Propofol is a widely used anesthetic agent with highly desirable fast "on" and "off" effects. It is currently formulated as lipid emulsions, which are known to support microbial growth. In this study, a novel, lipid-free nanodispersion formulation of propofol was characterized. The formulation was evaluated for its physical and chemical stability, in vitro compatibility with red blood cells, and its antimicrobial effectiveness. In vivo pharmacokinetic and pharmacodynamic properties of the formulation were evaluated in rats. Our data suggest that this lipid-free formulation is physically and chemically stable. Compared to the commercial emulsion formulation Diprivan, it causes less hemolysis with red blood cells and has improved antimicrobial activity. In addition, the lipid-free formulation demonstrates similar pharmacological effects to Diprivan in rats. This novel, lipid-free formulation exhibits improved in vitro properties without compromising in vivo effects, therefore representing a promising new alternative for propofol.

Formulation-dependent brain and lung distribution kinetics of propofol in rats.

Propofol when administered by brief infusion in a lipid-free formulation has a slower onset, prolonged offset and greater potency compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats. Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations. Peak propofol plasma concentrations for the lipid-free formulation were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher than emulsion formulation. Brain Kp calculated from tissue disposition curve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively. BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, respectively. Significant pulmonary sequestration and slow release of propofol into arterial circulation when administered in lipid-free vehicle accounts for the lower peak arterial concentration and sluggish arterial kinetics relative to that observed with the emulsion formulation. Higher Kp for the lipid-free formulation could explain the higher potency associated with this formulation. BT were independent of formulation and correlated with values reported for effect-site equilibration half-time consistent with a distribution mechanism for pharmacologic hysteresis.

This Month in ANESTHESIOLOGY

This Month in ANESTHESIOLOGY